Combination drug treatment for tuberculosis (TB) can extend over 6 months which provides the perfect setup for the development of drug resistant strains of M. tuberculosis (M.tb). With approximately 2 million new cases of TB each year, short course drug therapy would rapidly reduce the burden of M.tb infection and have significant impact on global public health. Targeting host responses during TB drug treatment is a novel approach to provide quicker and more effective drug treatment for TB. We hypothesize that IL-10 is the driver of the reported immune dampening properties of PZA, and that modification of IL-10 can be exploited to shorten the drug treatment time for M.tb infection. Our hypothesis is built upon preliminary data showing that PZA can clear M.tb infection to sterilization in IL-10 deficient mice within 45 days, a significant shortening of treatment time. We propose experiments to establish the causal relationship between PZA and IL-10 that accelerates the clearance of M.tb infection. These include blocking the action of IL-10 in vivo and investigating immune function during infection with a PZA resistant strain of M.tb. At the completion of these studies we will have determined the specific mechanism for how the anti-mycobacterial action of PZA is accelerated on an IL- 10 deficient background.